Currently, mechanistic understanding of the impact of phytochemical-rich diets on hypertension-associated heart failure is very limited. We used diets supplemented with freeze-dried whole grape powder to model a phytochemical-enriched diet. Preliminary studies show that a grape-enriched diet reduced cardiac oxidative damage, hypertrophy, and fibrosis and heart failure in the Dahl Salt-Sensitive (Dahl-SS) rat model of hypertension-associated heart failure. However, mechanisms of these effects remain unknown. Grape phytochemicals of broad interest include anthocyanins, flavanols (catechin, epicatechin, quercetin), and stilbenes (resveratrol). To elucidate mechanism, we will now compare the effects of whole grape powder to content-matched, isolated phytochemicals on Dahl-SS rat heart failure pathogenesis. Phytochemicals can activate peroxisome proliferator-activating receptors (PPAR). PPAR isoforms can reduce NFkB-related inflammation, and cardiac PPAR isoforms are down-regulated with heart failure. Phytochemicals can activate the NF-E2 p45-related factor (Nrf2) and the phenol-responsive Aryl-hydrocarbon receptor (AhR) which stimulates the gene transcription related to antioxidant defense. Our three-pronged central hypothesis is that in salt-fed Dahl-SS rats, 1) whole grape is superior to isolated phytochemicals in reducing cardiac fibrosis and improved cardiac index, 2) whole grape is superior to isolated phytochemicals towards cardiac AhR and Nrf2 activation and antioxidant gene expression, and 3) whole grape is superior to isolated phytochemicals towards enhanced cardiac PPAR activation and reduced NFkB activation. We will test the central hypothesis by the following two aims: (Aim 1) Compare Treatment Effects on Cardiac Endogenous Antioxidant Defense. Examine changes in cardiac AhR and Nrf2 nuclear translocation and the expression of XRE and ARE-related genomic targets related to antioxidant defense;(Aim 2) Compare Treatment Effects on Cardiac PPARs and Cardiac NFkB signaling. Examine changes in cardiac PPAR isoform activity and the expression of PPAR target genes. Measure nuclear NFkB and the expression of its genomic targets related to inflammation and fibrosis. Our long-term goal is to elucidate the relative cardiac effects of isolated phytochemical versus phytochemical- rich whole foods, using grapes as a model. The proposed studies are innovative because they go beyond transient effects and examine the accumulated, cardiac effects of a physiologically relevant, phytochemical- enriched diet or isolated phytochemical supplements on both healthy and diseased hearts. This proposed study is significant for public health with translational potential because findings could improve knowledge of the value of dietary and dietary supplement approaches for prevention of hypertension-associated cardiac pathology. In addition, our comparative studies may suggest classes of phytochemicals that provide superior cardioprotection. PUBLIC HEALTH RELEVANCE: Heart failure is a significant health burden that principally affects our aging population. The effect of diet on heart failure is poorly understood. Our long-term goal is to advance knowledge on the relative cardiac benefits of isolated phytochemical supplements versus phytochemical-rich whole foods.